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In a compact binary coalescence, the spins of the compact objects can have a significant effect on the orbital motion and gravitational-wave (GW) emission. For generic spin orientations, the orbital plane precesses, leading to characteristic modulations of the GW signal. The observation of precession effects is crucial to discriminate among different binary formation scenarios, and to carry out precise tests of General Relativity. Here, we work toward an improved description of spin effects in binary inspirals, within the effective-one-body (EOB) formalism, which is commonly used to build waveform models for LIGO and Virgo data analysis. We derive EOB Hamiltonians including the complete fourth post-Newtonian (4PN) conservative dynamics, which is the current state of the art. We place no restrictions on the spin orientations or magnitudes, or on the type of compact object (e.g., black hole or neutron star), and we produce the first generic-spin EOB Hamiltonians complete at 4PN order. We consider multiple spinning EOB Hamiltonians, which are more or less direct extensions of the varieties found in previous literature, and we suggest another simplified variant. Finally, we compare the circular-orbit, aligned-spin binding-energy functions derived from the EOB Hamiltonians to numerical-relativity simulations of the late inspiral. While finding that all proposed Hamiltonians perform reasonably well, we point out some interesting differences, which could guide the selection of a simpler, and thus faster-to-evolve EOB Hamiltonian to be used in future LIGO and Virgo inference studies.